SSRN - The SARS-CoV-2 Transcriptional Metabolic Signature in Lung Epithelium

[Gert van der Hoek]

Abstract


Viruses are efficient metabolic engineers that actively rewire host metabolic pathways to support their lifecycle. Charting SARS-CoV-2 induced metabolic changes in lung cells could offer insight into COVID-19 pathogenesis while presenting new therapeutic targets. Here we show that the transcriptional response SARS-CoV-2 in primary lung epithelial cells and biopsies of COVID-19 patients is predominantly metabolic. This transcriptional signature was dominated by changes to lipid metabolism and the induction of IRE1 and PKR pathways of endoplasmic stress in a process regulated by several viral proteins. Transcriptional regulatory analysis of these changes reveals small clusters of transcription factors modulating key enzymes in each pathway. The upregulation of glycolysis and the dysregulation of the citric acid cycle was mediated by NFκB and RELA. While the upregulation of fatty acid and cholesterol synthesis showed a more complex control conditionally modulated by ER-stress activated PPARγ, C/EBP, and PPARα. Viral protein ORF3a appeared to interact with all three pathways suggesting both direct and indirect modulation of host metabolism. Finally, we show that PPARα-agonist fenofibrate reversed the metabolic changes induced by SARS-CoV-2 blocking viral replication. Taken together, our data suggest that elevated lipid metabolism may underlie aspects of COVID-19 pathogenesis, offering new therapeutic avenues in targeting this critical pathway on which the virus relies.

Funding: Funding was provided by European Research Council Consolidator Grants OCLD (project no. 681870) and generous gifts from the Nikoh Foundation and the Sam and Rina Frankel Foundation (YN). This work was additionally funded by generous support from the Marc Haas Foundation, the National Institutes of Health, and DARPA’s PREPARE Program (HR0011-20-2-0040). The views, opinions, and/or findings expressed are those of the author and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. government (BRT).

Ethical Approval: Experiments using samples from human subjects were conducted in accordance with local regulations and with the approval of the institutional review board at the Icahn School of Medicine at Mount Sinai under protocol HS#12-00145.

 

[Gert van der Hoek]

Study finds fenofibrate may downgrade Covid-19 to common cold level

A study conducted by professor Yaakov Nahmias at Hebrew University in Israel has found that an existing cholesterol drug, fenofibrate, could ‘downgrade’ Covid-19 threat level to that of a common cold.

The findings allegedly come from lab tests on human lung tissue infected with SARS-CoV-2, the virus that causes Covid-19.

According to the research, the virus leads to deposits of lipids in the lungs. Nahmias partnered with Mount Sinai Medical Center researcher Dr Benjamin tenOever to gain better insights into SARS-CoV-2 mechanism of attack on the human body.

The researchers observed that the virus changes lipid metabolism in human lungs. They believe that halting this process could help prevent the onset of problems that increase the severity of the disease.

While SARS-CoV-2 hinders the ability of the body to break down fat, fenofibrate starts this process by binding and activating the DNA site that is blocked by the virus.


Nahmias was quoted by The Times of Israel as saying: “The interesting thing about our study is that fenofibrate actually binds and activates the very site on the DNA that the virus shuts down — a part of our DNA that allows our cells to burn fat.

“Virus infection causes the lung cells to start building up fat, and fenofibrate allows the cells to burn it.”

 

[Gert van der Hoek]

See also:

Combinations of Oseltamivir and Fibrates Prolong the Mean Survival Time of Mice Infected with the Lethal H7N9 Influenza Virus

PLoS ONE. Fenofibrate Reduces Mortality and Precludes Neurological Deficits in Survivors in Murine Model of Japanese Encephalitis Viral Infection